PROJECT SUMMARY The International Diabetes Federation estimates the global burden of diabetes to have skyrocketed to over 387 million people with healthcare costs reaching over $612 billion in the United States alone. Diabetes management for these individuals, particularly Type I Diabetic patients, is extremely rigorous and does not provide an efficient means of disease maintenance. Current standard of care for patients with Type I Diabetes is treatment with exogenous insulin, a measure, which simply put, allows patients to live normally, but does not inherently solve any of the underlying pathologies associated with the disease. Additionally, there are very few Type I Diabetes adjuvant therapeutics, none of which are known to improve ?-cell health and function. We have a growing body of evidence that suggests that this protein, specifically the alpha subunit (G?z) plays a notable role in mediating pathways regulating multiple ?-cell pathologies associated with Type I Diabetes. Therefore, our long-term goal is to fully elucidate the signaling mechanism by which G?z acts in both normal and diabetic ?-cells, determining the steps that become dysfunctional in the diabetic state, and ultimately modulating these steps for preventative and therapeutic purposes. The overall objective of this work, which is the next logical step in pursuit of our goal, is to characterize the role of ?-cell G?z on the molecular and cellular signaling pathways responsible for its impact on diabetes pathophysiology. Our central hypothesis is that activated ?-cell G?z negatively modulates specific intracellular and autocrine/paracrine signaling pathways critical for ?-cell compensation, ultimately leading to ?-cell dysfunction and loss of ?-cell mass resulting in diabetes pathogenesis. We will test our central hypothesis and, thereby, accomplish the objective of this application, by pursuing the following two specific aims: (1) Determine the role of ?-cell G?z on ?-cell function in the Type I Diabetic condition and (2) Elucidate the effect of ?-cell G?z on signaling pathways that mediate ?-cell survival following insulitis. With the completion of these aims, we anticipate a much more complete understanding of the role of G?z in both healthy and diabetic ?-cells. Such results are anticipated to have an important positive outcome on the diabetes field, as G?z is a unique player in the integrated signaling pathways that mediate ?-cell function and survival, providing a new target for developing therapeutics for the prevention and treatment of Type I diabetes.